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This version published online on August 4, 2005
Endocrinology, doi:10.1210/en.2005-0457
A more recent version of this article appeared on November 1, 2005
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Submitted on April 19, 2005
Accepted on July 29, 2005

Transforming Growth Factor Beta Activated Kinase1 (TAK1) is a Key Mediator of Ovine Follicle Stimulating Hormone Beta Subunit Expression

Nedal Safwat, Jun Ninomiya-Tsuji, A Jesse Gore, and William L. Miller*

Department of Molecular and Structural Biochemistry, Box 7622, North Carolina State University, Raleigh, NC 27695-7622; Department of Toxicology, Box 7633, North Carolina State University, Raleigh, NC 27695-7633

* To whom correspondence should be addressed. E-mail: wlmiller{at}ncsu.edu.

Follicle stimulating hormone (FSH), a key regulator of gonadal function, contains a {beta} subunit (FSH{beta}) that is transcriptionally induced by activin, a member of the transforming growth factor {beta} (TGF{beta}) superfamily. This study used 4.7 kb of the ovine FSH{beta} promoter linked to luciferase (oFSH{beta}Luc) plus a well characterized activin-responsive construct, p3TPLuc, to investigate the hypothesis that Smad3, TAK1 (TGF{beta} activated kinase1), or both cause activin-mediated induction of FSH. Over-expression of either Smad3 or TAK1 induced oFSH{beta}Luc in gonadotrope-derived L{beta}T2 cells as much as activin itself. Induction of p3TPLuc by activin is known to require Smad3 activation in many cell types and this was true in L{beta}T2 cells where 10-fold induction by activin (2-8 h after activin treatment) was blocked > 90% by two dominant negative (DN) inhibitors of Smad3 [DN-Smad3 (3SA) and DN-Smad3 (D407E)]. By contrast, 6.5-fold induction of oFSH{beta}Luc by activin (10-24 h after activin treatment) was not blocked by either DN-Smad inhibitor, suggesting that activation of Smad3 did not trigger induction of oFSH{beta}Luc. By contrast, inhibition of TAK1 by a DN-TAK1 construct led to a 50% decrease in activin-mediated induction of oFSH{beta}Luc, and a specific inhibitor of TAK1 (5Z-7-Oxozeanol) blocked induction by 100% indicating that TAK1 is necessary for activin induction of oFSH{beta}Luc. Finally, inhibiting p38-mitogen activated protein kinase (p38-MAPK; often activated by TAK1) blocked induction of oFSH{beta}Luc by 60%. In conclusion, the data presented here indicate that activation of TAK1 (and probably p38-MAPK), but not Smad3, is necessary for triggering induction of oFSH{beta} by activin.
Key words: Follicle Stimulating Hormone (FSH) • Transforming Growth Factor Beta Activated Kinase-1 (TAK1) • Activin • Gonadotropes




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